Early Hepatitis C viral (HCV) kinetics was previously shown to predict sustained virological response (SVR). The current consensus stopping rule is defined at 12 weeks of treatment with peginterferon-alfa and ribavirin. Earlier prediction is needed in order to improve the cost/effect ratio. However, the predictive value of earlier viral kinetics for the current standard of care has not yet been established.
 

The DITTO-HCV European funded project is for now the largest study of frequent early viral kinetics during therapy with peginterferon-alfa and ribavirin. The researchers aim to optimize viral kinetics prediction criteria in order to enable stopping or tailoring treatment as early as possible.

Primary objectives: 1) negative predictive value (NPV) as close as possible to 100% (thus minimalizing stopped patients with missed SVR), 2) high specificity (thus increasing the fraction of patients that can be safely stopped). 3) a high positive predictive value (PPV) using the same criteria.
 

134 chronically HCV infected naïve patients received peginterferon-alfa-2a (40KD) (Pegasys ®) (180 μg qw) plus ribavirin (Copegus ®) (1000-1200 mg qd) for 48 weeks. Of those, 67%, 28%, 4% and 1% had HCV genotype 1, 2-3, 4 or 5 respectively. Viral kinetics were measured according to centralized serum HCV RNA quantifications on days 0, 1, 4, 7, 8, 15, 22 and 29 (Cobas Amplicor^® HCV Monitor v2, Roche). SVR was defined as undetectable serum HCV RNA (<50 IU/ml) after 24 weeks of follow-up post treatment. The early viral response prediction criteria (EVR) and thresholds tested here (see Table 1 below) were prospectively defined.

Study Results

The overall SVR rate was 64%. The EVR studied, together with their NPV, PPV, specificity (SP), statistical significance and number of HCV-RNA quantifications needed (NSMP), are given in Table 1 below.

TABLE 1

The EVR-w12 criteria has good NPV (100%) but its specificity is low (21%), thus relatively few non-responders can be stopped. None of the simple 2nd-slope or Week-1 criteria shows NPV higher than 90%, thus not adequate for a stopping rule.

 

A new composite criteria (DITTO-2nd-slp) gives NPV=100% and specificity=34% already after 4 weeks of treatment. Furthermore, another new composite criteria (DITTO-1st-week) also gives NPV=100% with specificity=28% already after 1 week.

Although composite, these new criteria are simple to calculate and necessitate only 1 or 2 more viral quantifications compared to the current Week-12 criteria. Thus allowing to lower the mean cost by 2410 USD per patient. Note that SVR (56% for gen 1 and 87% for gen 2-3) is predicted independently of genotype.

 

Moreover, by selecting more strict thresholds for the DITTO-1st-week (e.g. 4.5 log at day 4 and 2 log decline at day 7) and DITTO-2nd-slope (e.g, 0.6 log/week) criteria one can obtain higher PPV up to 90%.

 

Conclusions:

Sustained viral response to treatment with peginterferon-alfa-2a (40KD) and ribavirin can be predicted, independent of genotype, as early as 1 or 4 weeks of treatment by new composite, but still simple and practical, criteria of viral kinetics. Similar NPV and PPV and better specificity was obtained here by the DITTO-1st-week or DITTO-2nd-slope prediction criteria, giving rise to significantly lower cost/effect as compared to the current stopping rule at 12 weeks. These results warrant future prospective testing in larger trials, since they can give rise to considerable saving in cost and quality of life related to over-treatment or alternatively allow early tailoring of treatment.

Discussion

Can the new predictive criteria move the current 12- week stopping rule to under a month?

The DITTO-HCV study retrospectively identified two new criteria to classify rapid viral responders and predict the likely treatment outcome. For the DITTO-1^st week criterion viral levels are measured at baseline and two times in the first week of treatment; while the DITTO-2^nd slope criterion uses three measurements of viral levels between the second and fourth week of treatment. 

“Both of these new criteria predicted who was and who was not likely to respond to treatment more accurately than the existing 12-week stopping rule. We had obtained 100 per cent negative predictive value (NPV) and 90 per cent positive predictive value (PPV) with these criteria” said Professor Avidan Neumann, from the Bar-Ilan University, Israel, and the DITTO-HCV study coordinator who presented the study results at an oral session at AASLD.

Using these criteria for stopping treatment in patients predicted early on not to respond will make treatment more cost-effective, even considering the added cost of the extra measurements of viral load.

“This is good news for patients and physicians.  Using these new criteria, we will be able to very early, identify more of those patients who will ultimately not achieve an SVR so we can advise them to stop taking their medication, thus improving their quality of life,” said Professor Neumann.

“We now know that tailoring treatment according to viral kinetics cannot improve SVR rates with the treatment choices we have at the moment.  However, by measuring viral levels earlier in treatment, a test physicians are already familiar with, we can likely move the stopping rule currently defined at week 12 down to week 4 or even week 1 and avoid having patients who will not achieve an SVR being treated unnecessarily. These novel prediction algorithms will hopefully be confirmed soon by other clinical trials and their feasibility in clinical practice will be assessed, thus allowing us to optimize the treatment of hepatitis C patients," concluded Prof. Neumann. 

10/27/03

Reference
AU Neumann and others. EARLY VIRAL KINETICS PREDICTION OF SUSTAINED VIROLOGICAL RESPONSE AFTER 1 OR 4 WEEKS OF PEG-INTERFERON-ALFA-2A AND RIBAVIRIN THERAPY (DITTO-HCV PROJECT).

Pegasys/Ribavirin Treatment in African American and Caucasians with Chronic HCV Genotype 1
 

Background: Response rates to interferon (IFN) therapy appear to be lower in African American (AA) patients with chronic hepatitis C than in Caucasians (Ca). The lower response has been attributed, in part, to the high prevalence of infection with hepatitis C virus (HCV) genotype 1 among the AA population. However, low numbers of AA patients in prospective clinical trials has hampered meaningful evaluation of antiviral therapy.

 

The objective of this study was to determine the efficacy and safety of Pegasys (peginterferon alfa-2a/40KD) in combination with ribavirin (RBV) in non-Hispanic AA HCV genotype 1 patients.

The trial enrolled patients in a 3:1 ratio of AA to Ca patients and was powered only to estimate sustained virologic response (SVR) in the AA group to within ± 10% of a 95% confidence interval.
 

Patients with previously untreated chronic HCV genotype 1 and elevated ALT received Pegasys 180 µg sc once weekly plus RBV 1000 or 1200 mg orally based on body weight (<75 kg or >75 kg) for 48 weeks, with 24 weeks of treatment-free follow-up. High viral load (HVL) was defined as HCV RNA >1 X 10⁶ IU/mL.

Early virologic response (EVR) at 12 weeks of therapy (defined as HCV RNA <50 IU/mL, or >2-log₁₀ drop in HCV RNA from baseline) was assessed. SVR was defined as undetectable HCV RNA at week 72; sustained biochemical response (SBR) was defined as normal serum ALT at Week 72.

Histologic responses were reported as Knodell HAI scores of liver biopsies obtained prior to treatment and within 4 weeks of completion of the 24-week untreated follow-up period.
 

Study Results

A total of 106 patients received at least one dose of study medication. Baseline characteristics of AA patients were: mean age 46 years, 56 male (72 %), mean ALT 63 U/L, high viral load 45 (58%).

Baseline characteristics of Ca patients were: mean age 45 years, 17 male (61%), mean ALT 64 U/L, high viral load 12 (43%). Sixty-two of 78 (80%) AA patients and 22 of 28 (79%) Ca patients completed treatment. The table below shows an SVR rate of 26% for AA patients and 39% for Ca patients.

A larger proportion, 45 of 78 AA patients had high viral loads prior to the initiation of therapy, contrasting with only 12 of 28 Ca patients.

SVR was achieved by 9 (20%) and 3 (25%) of patients with HVL in each group respectively. Of 47 AA patients who had EVRs, 20 patients went on to achieve an SVR.

The negative predictive value of EVR was 100% for both AAs and Cas. SBR was observed with similar frequency for both racial groups (36% for AA and 39% for Ca). Histologic analyses of a subgroup of patients for whom paired biopsies were available showed that 13 of 53 (25%) AA patients and 1 of 16 (6%) Ca patients had fibrosis improvement. No unexpected adverse events (AEs) occurred during the study. Four of 78 (5%) AA patients and 4 of 28 (14%) Ca patients withdrew prematurely for AEs or laboratory abnormalities.
 

Conclusions

The SVR of 26% in AA with genotype 1 HCV after therapy with Pegasys plus RBV is the highest response to combination therapy yet reported in this population. The SVR rate in the AA population is nonetheless lower than in other studies with patients of diverse ethnic backgrounds and may be explained by the higher viral titers observed in these patients. Failure to achieve EVR has a high negative predictive value for SVR with continuing therapy.

This study demonstrates that Pegasys with RBV is a safe and tolerable treatment for AA patients with chronic HCV genotype 1 infection. In addition, the SVR rate and histologic benefit observed in this trial provide a basis for future efforts to increase efficacy in this difficult to treat population .

Summary of Efficacy Analyses

Louisiana State University Health Sciences Center, University of Maryland School of Medicine, University of Pennsylvania, Roche Laboratories, Inc., Nutley, NJ.

10/27/03

Reference
LJ Jeffers and others. Peginterferon Alfa-2a (40KD) (Pegasys^®) in Combination with Ribavirin in African American and Caucasian Patients with Chronic Hepatitis C Virus Genotype 1: Results of a Multicenter Study.  Abstract 71 (oral). 54^th AASLD. October 24-28, 2003. Boston, MA.

Pegasys/Ribavirin Enhances HCV Specific T-cell Responses by Restoration of Dendritic Cell Functions
 

Pegasys (peginterferon alfa-2a/40KD)/ribavirin combination therapy markedly improves the sustained virological response in chronic hepatitis C compared to conventional interferon alfa therapy.

This research group has previously demonstrated that Pegasys alone or in combination with ribavirin enhances HCV specific CD4+ T helper 1 responses in patients with chronic hepatitis C but the underlying mechanism by which the HCV-specific responses are restored is not yet fully understood.

Dendritic cells (DCs) are the most efficient type of cells involved in antigen presentation (APC), however HCV proteins affect DC function resulting in abnormal priming of anti-HCV-specific T cells and defective antiviral immunity. The investigators hypothesized that peginterferon activates CD4⁺ T cells through restoration of the DC antigen-presenting function.

Monocyte-derived dendritic cells (DCs) generation (magnatic sorting and positive selection), phenotypic analysis and allogeneic stimulatory capacity of DC (S.I.) as well as HCV-specific CD4+ T-cell proliferative responses and cytokine production to HCV proteins (ELISPOT assay using autologous DCs as APCs) were prospectively assessed in 64 patients with chronic hepatitis C (genotypes 1 and 4) before, during and after treatment with either conventional IFN-alfa-2a therapy, or Pegasys/ribavirin combination therapy and the results were correlated to the therapy outcome.

Study Results

 The SVR in genotype 1 was 49% with Pegasys/ribavirin, and 26% with conventional IFN alfa-2a ribavirin while in genotype 4 the SVR was 54% in subjects treated with Pegasys/ribavirin combination therapy vs 28% of HCV in subjects treated with conventional IFN alfa-2a/ribavirin.

Before induction of therapy, DCs from HCV infected subjects exhibited a pattern of incomplete activation and the stimulatory capacity of HCV-DCs was significantly lower than that of the normal-DCs (7.8± 3.9 vs. 67.2± 19.7, respectively; P < 0.001)

The same pattern of incomplete activation was observed in CD4⁺ T cells in the form of absent or weak pre-treatment HCV specific CD4⁺ responses. Initiation of Pegasys/ ribavirin therapy markedly ameliorated the allostimulatory capacity in DCs of HCV patients and induced significant increase in the frequency, strength and breadth of HCV-specific CD4+T-h1 responses; compared to conventional IFN-alfa-2a-based regimen.

The stimulatory capacity of HCV-DC was restored to normal in subjects who achieved SVR (62.05 ± 17.7 in SR versus 11.88 ± 2.55 in NR; P = 0.007).

Sustained responders developed early restoration of DC functions and strong multi-specific persistent HCV specific CD4+T- cell responses with preferential IFN-γ production and IL-10 suppression. Interestingly patients who had breakthrough or relapse had transient increase in DC stimulatory capacity, which coincided with the absence of HCV viremia; however DC abnormalities were detected with recurrence of viremia.

Viral clearance and HAI improvement but not HCV genotype correlated with the DC stimulatory capacity and HCV-specific CD4⁺ responses. 

The authors conclude, “Pegasys in combination with ribavirin enhances HCV specific CD4⁺ T responses through restoration of the antigen presenting functions of dendritic cells. This finding has important implications for development of novel immunotherapeutic strategies.

Harvard Institutes Of Medicine, Boston, Ma, USA, University Of Freiburg, Germany, Ain Shams University, Egypt.

10/26/03

Reference
SM Kamal and others. PEGINTERFERON a-2A (40KD) ENHANCES HCV SPECIFIC T-CELL RESPONSES BY RESTORATION OF ALLOSTIMULATORY FUNCTION of DENDRITIC CELL FUNCTIONS IN CHRONIC HEPATITIS C. Abstract 63 (oral). 54^th AASLD. October 24-28, 2003. Boston, MA.

Preliminary Data Do Not Support Hypothesis That Higher SVR Rates in Genotype 1 HCV Patients Result from Extending Treatment from 48 to 72 Weeks

Treatment of patients infected with hepatitis C virus (HCV) genotype 1 (G1) remains a challenge necessitating innovative strategies to improve treatment outcome. Viral kinetic studies have shown that turnover of hepatocytes infected with HCV G1 is slower than in other genotypes. This implies that more aggressive antiviral treatments are required in patients infected with HCV G1.

Extending the treatment duration beyond 48 weeks is one strategy that may improve response rates in these difficult-to-treat patients.
The purpose of the current study was to compare the efficacy and safety of 48 weeks versus 72 weeks of treatment with peginterferon alfa-2a (40KD) (PEGASYS) in combination with ribavirin (COPEGUS) in treatment-naïve patients infected with HCV G1.
 

This multicenter, national, randomized, open-label parallel group study was conducted in accordance with local and international GCP guidelines. Treatment-naïve patients infected with HCV G1, aged ≥18 years with CHC infection, HCV RNA levels >1000 copies/mL, elevated ALT levels, liver biopsy findings consistent with a diagnosis of CHC, and compensated liver disease (Child-Pugh grade A) were eligible for the study.
 

After screening and signing of informed consent forms, patients were randomized to treatment with peginterferon alfa-2a (40KD) (PEGASY) 180 μg once weekly plus ribavirin (COPEGUS) 800 mg/day (400 mg BID) for either 48 weeks or 72 weeks. Patients were followed for an additional 24 weeks after the end of treatment. Virological response was defined as undetectable HCV RNA (<50 IU/mL by COBAS AMPLICOR HCV Test, v2.0, Roche Diagnostics) at the end of follow-up.
 

To date 459 patients have been enrolled in the trial and 305 have completed follow-up. The two treatment groups were comparable with regard to baseline characteristics. The results of the study, presented as intent-to-treat, missing data = failure (ITT; M=F), and on-treatment (OT) analysis (only patients with data included) are captured in the Table 1 below.
No major differences were observed in the frequency or intensity of SAEs and AEs.
 

Conclusions

The combination of peginterferon alfa-2a (40KD) (PEGASYS) and ribavirin (COPEGUS) was safe and effective in patients with HCV genotype 1. Despite the use of a dose of ribavirin (800 mg/day) that is lower than the recommended dose for patients infected with G1 (1000/1200 mg/day), approximately half of the patients in the study achieved an SVR.

Because the study could not be blinded, a bias might have influenced the outcome of the study as suggested by the unequal discontinuation rate. These preliminary data do not support the hypothesis that higher SVR rates can be achieved in patients with HCV G1 by extending treatment duration.

^{*ITT population, defined as all patients who took at least one dose of study medication and had at least one HCV RNA evaluation post-baseline.
**Safety population, defined as all patients who took at least one dose of the study medication.}

10/27/03

Reference
T Berg and others (German Pegasys + Copegus Genotype 1 HCV Study Group). COMPARISON OF 48 OR 72 WEEKS OF TREATMENT WITH PEGINTERFERON ALFA-2A (40KD) (PEGASYS^®) PLUS RIBAVIRIN (COPEGUS^®) IN TREATMENT-NAÏVE PATIENTS WITH CHRONIC HEPATITIS C INFECTED WITH HCV GENOTYPE 1. Abstract 328 (poster). 54^th AASLD. October 24-28, 2003. Boston, MA.

Subjects with Chronic Hepatitis C and Genotype 4 Have a Similarly Effective Response to Standard or Pegylated Interferon in Combination with Ribavirin
 

The prevalence of HCV infection in Egypt varies between 9% and 24% and approximately 90% are infected with HCV genotype 4.To date limited data exist on the effect of antiviral therapy on genotype 4-infected subjects.

The purpose of this study was to assess the effect of interferon (standard or pegylated) in combination with ribavirin in naïve-to-treatment subjects with chronic hepatitis C who reside in Egypt.

In a prospective, open-label, randomized clinical trial, 200 Egyptian subjects with chronic hepatitis C documented by liver biopsy and detectable HCV RNA in serum received interferon alfa 2b (IFN-a2b) 3 MU TIW or pegylated IFN-a 2b (100 mcg/week) in combination with weight-based oral ribavirin (800 or 1000 mg for both groups).

The study design was that if HCV RNA was detectable at week 24, the treatment was stopped but if HCV RNA was undetectable at week 24, treatment was extended for a total of 48 weeks. Subjects were observed for an additional 24 weeks and HCV RNA status at week 72 determined the response to antiviral therapy.

Safety laboratory tests were done at regular intervals. The study received IRB approval. The HCV RNA was done by a PCR technique with a detectability cutoff of 50-copies/ml.

Study Results

Both randomized groups were similar at baseline without statistical significant difference, 190 (90%) were infected with genotype 4, mean age was 39.5 years ± 8.7 years, 158 were men (79%), mean BMI was 27.8 ± 4 kg/m², mean inflammatory HAI score was 7/18 ± 2 and fibrosis stage 2.7/6 ± 1.3.

Of the 190 genotype-4 infected individuals, 156 have finished therapy (week 48) and 78 had completed the 24-week follow-up (week 72). The study will be completed by October 2003. The table shows the intention to treat rates of undetectable HCV RNA in genotype-4 infected subjects.

Serious adverse events that led to discontinuation of medications were observed in 6 subjects in the standard IFN/RBV group and in 11subjects in the PEG IFN/RBV, one death was observed in the latter group. Expected adverse events were observed in similar rates in both groups.

Laboratory adverse events were observed between 2% and 10% of subjects receiving either treatment regimen depending on the week of therapy. No growth factors were used in this population.

Conclusions

Subjects with chronic hepatitis C and genotype-4 infection have a similar antiviral response to standard or pegylated interferon in combination with ribavirin. The safety and tolerability of the medications is similar to what has been observed for other HCV genotypes. Patients infected with HCV genotype 4 respond effectively to therapy and should be encouraged to undergo antiviral treatment.

10/27/03

Reference
GH Esmat and others. RESULTS OF A RANDOMIZED CLINICAL TRIAL OF GENOTYPE-4 INFECTED SUBJECTS WHEN TREATED WITH STANDARD OR PEGYLATED INTERFERON alfa-2b IN COMBINATION WITH RIBAVIRIN. Abstract 324. 54^th AASLD. October 24-28, 2003. Boston, MA.

Rapid Viral Decline with Pegasys/Ribavirin in HCV Genotype 1 Is Associated with Enhanced HCV-specific T-cell Reactivity
 

By Brian Boyle, MD

Treatment of patients with chronic HCV infection with HCV genotype 1 (GT 1) remains a significant challenge, with patients infected with this genotype having significantly lower rates of response to therapy relative to patients infected with genotypes 2 or 3. The reasons for this poor treatment response are not well understood and therapeutic optimization requires an understanding of the differences in viral dynamics and immune reactivity during therapy.
 

In a study presented at the 54^th AASLD Conference, investigators analyzed early HCV kinetics during Pegasys (peginterferon-alfa 2a) plus ribavirin treatment and their relationships with both cellular and humoral immune responses in 30, treatment-naïve, non-cirrhotic, GT 1 infected patients.
 

The investigators found that at treatment week (TW) 4, 19/30 (63%) patients showed >2 log₁₀ copies/mL reduction from baseline viral load and 28/30 (93%) patients achieved >2 log₁₀ copies/mL reduction in viral load at TW 12.

Mathematical modeling of serial plasma viral load measurements clearly differentiated two subgroups - rapid (19/30) and slow/flat (11/30) treatment-responders over the first 4 weeks of antiviral treatment.

The novel triphasic pattern of HCV decay was found in 10/19 (52%) rapid responders, and 5/11 (45%) of slow/flat responders. The phase 1 viral decline and infected hepatocyte clearance were significantly higher in rapid, compared to slow/flat responders.

Anti-E1 levels decreased by 22% between baseline and TW 4 with no significant differences between rapid vs slow/flat responders. Baseline gamma GT and TW 4 viral load were significantly lower in rapid versus slow/flat responders (p<0.05).

Based upon these data, the authors conclude, “This study reveals marked differences in early viral kinetic profiles amongst [GT 1] patients treated with peginterferon-alfa 2a and ribavirin. Rapid viral decline after starting treatment is associated with enhanced HCV-specific T-cell reactivity. HCV dynamics and associated immune reactivity during therapy enables optimization of treatment regimens in patients with [GT 1] infection.”

Reference
K Tang and others. RELATIONSHIP BETWEEN EARLY VIRAL KINETICS AND IMMUNE REACTIVITY IN CHRONIC HEPATITIS C (GENOTYPE 1) PATIENTS TREATED WITH PEGINTERFERON-ALFA 2A AND RIBAVIRIN. Abstract 191 (oral). Program and Abstracts of the 54^th Annual Meeting of the American Association for the Study of Liver Diseases.  October 24-28, 2003. Boston, MA.

Combination Treatment with Pegasys and Copegus Significantly Enhances Sustained Virological and Biochemical Response Rates in Patients with Chronic Hepatitis C Genotype 4

Hepatitis C genotype 4 accounts for 60 to 90% of HCV chronic infections in the Eastern Mediterranean region but this is rare in other parts of the world. Earlier studies have reported poor treatment response rates for conventional interferons (IFN) with HCV genotype 4.

The advent of pegylated IFN and its success with other genotypes was our motivation for the current study. The objective was to determine and compare the efficacy and safety of Pegasys (peginterferon alfa-2a) plus ribavirin with Pegasys monotherapy and Roferon A (IFN alfa-2a) plus ribavirin combination therapy in the treatment of chronic hepatitis C genotype 4 patients in Saudi Arabia.
 

This open label multicenter clinical enrolled 180 patients infected with chronic hepatitis C genotype 4. These patients were randomized into treatment groups (1:1:1) as follows:
 

GROUP A: Pegasys 180micrograms qw plus ribavirin (400mg) bid.
GROUP B: Pegasys 80 micrograms qw.
GROUP C: Roferon 4.5MIU tiw plus ribavirin (400mg) bid.

Treatment duration was for 48 weeks with follow up period of 24 weeks.
 

Study Results

Early virological response (2-log drop or HCV-RNA clearance) at week 12 was 77%, 60% and 43% in groups A, B and C, respectively. End of treatment response (week 48) for the groups were 67%, 59% and 37%.

Sustained virological responses (week 72) were 50%, 28% and 30% respectively.

Among week 12 early responders the sustained virological responses were 65.2% and 47.2% in the two-pegylated IFN groups and the sustained biochemical response was 69.6% and 69.4%.

Twelve patients (6.7%) dropped out of the study as follows: group A, 7 patients (11.7%), group B, 4 (6.7%) and group C, 1 (1.7%). These were various adverse events ranging from alopecia, thyroiditis, oesophageal varices, tonic convulsion, encephalopathy and depression. Interestingly 5 of the 12 patients had early virological response.
 

Conclusions

a) A 100% negative predictive value among non-responders was observed for all treatment groups at early virological response at week 12.
b) Despite the use of a low dose ribavirin of 400mg bid, an enhanced sustained virological response of 50% (65% in early responders) was determined for the combination of peginterferon alfa-2a plus ribavirin.
c) A comparatively low relapse rate was observed in patients treated with peginterferon alfa-2a plus ribavirin.
d) Patients infected with HCV genotype 4 can be safely and effectively treated with Pegasys plus Copegus (ribavirin).

11/05/03

Reference
OA Shobokshi COMBINATION THERAPY OF PEGINTERFERON ALFA-2A (40KD) (PEGASYS®) AND RIBAVIRIN (COPEGUS®) SIGNIFICANTLY ENHANCE SUSTAINED VIROLOGICAL AND BIOCHEMICAL RESPONSE RATE IN CHRONIC HEPATITIS C GENOTYPE 4 PATIENTS IN SAUDI ARABIA. Abstract 996 (poster). 54^th Annual Meeting of the American Association for the Study of Liver Diseases. October 24-28, 2003. Boston, MA

Pegasys Plus Ribavirin Demonstrates Good Safety and Tolerability Profiles in African Americans with Chronic HCV Genotype 1

Interferon alfa therapy, alone or in combination with ribavirin (RBV), is less effective for chronic hepatitis C genotype 1 infections in African Americans (AA) compared with Caucasian Americans (Ca). Racial differences in tolerability and adherence to antiviral therapy have not been studied systematically. Several studies on treatment of African Americans with chronic HCV genotype 1 were presented at the 53^rd AASLD in Boston (October 24-28, 2003).

The aim of the current study was to evaluate the safety and tolerability of peginterferon alfa-2a (40KD) when used in combination with ribavirin in non-Hispanic AA HCV genotype 1 patients.
 

Patients with previously untreated chronic hepatitis with HCV genotype 1 and elevated ALT were evaluated. Patients received Pegasys (peginterferon alfa-2a) 180 microgram subcutaneous (sc) once weekly plus RBV 1000 or 1200 mg orally based on body weight (<75 kg or >75 kg) for 48 weeks, with 24 weeks of treatment-free follow-up.

Efficacy was assessed by sustained virologic response (SVR), defined as undetectable HCV RNA (<50 IU/mL) at week 72. Adverse events (AEs) reported by patients and clinical laboratory test results were used to assess tolerability and safety.
 

Study Results

A total of 106 patients received at least one dose of study medication. Of patients completing treatment, 62 of 78 (80%) were AA and 22 of 28 (79%) were Ca. The SVR rate (26%) was lower among AA patients than among Ca patients (39%). The most frequent AEs reported included headache, fatigue, rigors, insomnia, nausea, myalgia, arthralgia, pyrexia, depression, dizziness, irritability, dyspnea and injection site erythema; most reported at a higher frequency by Ca than by AA.

Serious AEs occurred in 9% (7 of 78) of AA patients and in 25% (7 of 28) of Ca patients; however, only 3 were considered to be treatment-related by the investigators (thrombocytopenia, upper abdominal pain and possibly hydronephrosis).

AA patients had lower baseline absolute neutrophil counts (ANC) (AA 2.9 ± 0.15 x 10⁹/L vs. Ca 3.5 ± 0.19 x 10⁹/L). Reductions in ANC by 45% for AAs were observed after one week of therapy, sustained during treatment, and returned to pretreatment levels early in the follow-up period. A gradual 51% decline in ANC occurred by week 6 for the Ca patients. The ANC nadir for AA was 1.6 + 0.09 x 10⁹/L, similar to that for Cas, 1.7 + 0.10 x 10⁹/L.

Similar results on treatment and during follow-up were observed for hemoglobin (Hb) and platelet counts. Hb levels decreased to to <8.5 g/dL in 4 (5%) AA patients and 2 (7%) Ca patients.

Platelet counts <50 x 109/L (not associated with bleeding-related adverse events) were evident in 3 (4%) AA patients and 1 (4%) Ca patient. Dose modifications of Pegasys (withheld or reduced) occurred among 46% AAs and 29% Cas; the most common indication was neutropenia (37% and 18% among AAs and Cas, respectively). RBV dose modifications occurred for 40% of AAs and 46% of Cas, primarily due to anemia.

Few patients withdrew prior to the end of treatment at week 48 for AEs or laboratory abnormalities, 4 of 78 (5%) in the AA group and 4 of 28 (14%) in the Ca group.

Discontinuations due to hematologic suppression were as follows: 1 AA patient for neutropenia, 1 AA patient for anemia and 1 Ca patient for thrombocytopenia.

One AA patient died as a result of an acute anterior myocardial infarction 180 days after receipt of the last dose of RBV. The death was considered to be unrelated to treatment by the investigator.

Large majorities of both groups, 67 (86%) of AA patients and 25 (89%) of the Ca patients demonstrated 80% adherence to the therapeutic regimen, calculated as total cumulative dose/total original dose prescribed, indicating that compliance was similar between racial groups.
 

Conclusions

Pegasys plus RBV demonstrated good safety and tolerability in AA patients in this trial. While dose modifications for neutropenia and anemia were conducted according to protocol, hematologic suppression had minimal effects on overall adherence to therapy. Adverse events were generally mild.

11/03/03

Reference
C Howell and others. PEGINTERFERON ALFA-2A (40KD) (PEGASYS^®) IN COMBINATION WITH RIBAVIRIN IN AFRICAN AMERICAN AND CAUCASIAN PATIENTS WITH CHRONIC HEPATITIS C HCV GENOTYPE 1: SAFETY AND TOLERABILITY. Abstract 332 (poster). 54^th Annual Meeting of the American Association for the Study of Liver Diseases. October 24-28, 2003. Boston, MA.

Pegasys Plus Ribavirin Produces a Benefit Regarding Histologic Response Among African Americans and Caucasians with Chronic HCV Genotype 1

Chronic hepatitis due to hepatitis C virus (HCV) is common among African Americans (AA) and HCV genotype 1 accounts for approximately 90% of HCV infections in these individuals. Virologic response rates to interferon (IFN) therapy in AA patients with chronic HCV infection have been reported to be lower than that for Caucasians (Ca), but the effect of therapy on hepatic histology in AA patients remains to be assessed.
 

The objective of this open label study was to evaluate histologic progression of disease in conjunction with anti-viral efficacy and safety in non-Hispanic AA HCV genotype 1 patients and non-Hispanic Ca, HCV genotype 1 patients treated with Pegasys (peginterferon alfa-2a/40KD) in combination with ribavirin (RBV).
 

A multicenter study was conducted to evaluate the efficacy and safety of the combination of Pegasys and RBV in AA patients and in Ca patients. All patients were required to have previously untreated chronic HCV genotype 1 infection, elevated ALT levels and. a liver biopsy obtained within the 24 months prior to enrollment demonstrating chronic hepatitis but without cirrhosis.

Patients received Pegasys 180 microgram sc once weekly plus RBV 1000 or 1200 mg orally based on body weight (<75 kg or =75 kg) for 48 weeks, with 24 weeks of treatment-free follow-up.

Histologic responses based on the Knodell HAI score were determined from liver biopsies obtained prior to treatment and within 4 weeks of completion of the 24-week untreated follow-up period. HAI activity scores range from 0-18 and fibrosis scores range from 0-4. The histology outcome was evaluated for patients with paired biopsies only.

Improvement in necroinflammatory activity was defined as >2 point decrease, and improvement in fibrosis as > 1 point decrease. The primary efficacy endpoint was sustained virologic response (SVR) with undetectable HCV RNA (<50 IU/mL) at 72 weeks.
 

Study Results

The intent-to-treat population included 106 patients. Paired biopsies were available for 53 of the 78 AA patients and 16 of the 28 Ca patients. These patients were representative of all patients with respect to Knodell HAI scores.

Mean baseline HAI activity scores were 7.2 + 0.32 for AA and 6.9 + 0.69 for Ca patients; mean baseline fibrosis scores were 1.8 + 0.14 and 1.9 + 0.3, respectively. The SVR rate for all AA patients was 20/78 (26%) and for all Ca patients, 11/28 (39%).

For those patients with paired biopsies, SVR rates were 17/53 (32%) in AA patients and 10/16 (63%) in Ca patients. The majority of patients in both groups exhibited improvement in activity scores: 64% for the AA group and 69% for the Ca group.

More importantly, the table below shows that the proportion of patients with worsening fibrosis was similar in both groups, while 13/53 (25%) of AA patients and only 1/ 16 (6%) of Ca patients showed fibrosis improvement. Mean changes in fibrosis scores were -0.4 ± 0.14 for AA and -0.1 ± 0.14 for Ca patients.

Among AA patients who had paired biopsies, 5/17 (29%) patients who achieved SVR had fibrosis improvement; and 8/36 (22.2%) viral non-responders exhibited fibrosis improvement. The only patient who had fibrosis improvement among Ca was a viral non-responder.
 

Conclusions

Therapy with Pegasys plus RBV produced improvement in necro-inflammation and fibrosis in a substantial group of AA patients in this study. Although the SVR of 26% in AA with genotype 1 HCV is the highest response to combination therapy yet reported in this population, even patients without an SVR achieved a benefit with regard to hepatic histology.

11/03/03

Reference
W Cassidy and others. PEGINTERFERON ALFA-2A (40KD) (PEGASYS^®) IN COMBINATION WITH RIBAVIRIN IN AFRICAN AMERICAN AND CAUCASIAN PATIENTS WITH CHRONIC HEPATITIS C VIRUS GENOTYPE 1 INFECTION: ASSESSMENT OF HISTOLOGIC RESPONSE. Abstract 307 (poster). 54^th Annual Meeting of the American Association for the Study of Liver Diseases. October 24-28, 2003. Boston, MA.

Daily and Higher Initial Dosing of Consensus Interferon (Infergen) May Be a Worthwhile Alternative to Peginterferon + Ribavirin in Genotype 1 HCV Patients with High HCV RNA

Treatment with pegylated interferon alfa and ribavirin has an efficacy in chronic hepatitis C patients with sustained response rates of about 50%. However, response in genotype 1 patients with high viral load is considerably lower and is not significantly improved by pegylation of interferon.

In the present study, conducted at the University of Tubingen, Germany, the efficacy of consensus interferon (CIFN) daily dosing and induction therapy followed by combination with ribavirin in 200 naive patients with chronic hepatitis C and genotype 1 was evaluated.

All patients had histologically proven hepatitis, elevated ALT values and were viremic, the average weight was 80 kg. Patients were treated with CIFN dosages of 27 or 18 ug QD for 4 weeks, followed by 18 or 9 ug QD for 8 weeks. Treatment was continued with CIFN at 9 ug QD with ribavirin (7.5 or 15 mg/kg/d) for another 36 weeks.
 

Study Results

At 48 weeks therapy an undetectable HCV-RNA was observed in 79 % and 72 % in the CIFN 27/18 and 18/9 ug groups, respectively. Data regarding sustained response rates showed 64% and 58% for CIFN 27/18 and 18/9 ug groups, respectively. Due to side effects CIFN had to be dose reduced in 11% and discontinued in 6% of patients.

Addition of ribavirin potentiated the effect of consensus interferon in a dose-dependent manner as has been shown for other interferons previously.

When viral response rates were related to the initial viral load, in the genotype 1 / low viral load group, SR rates of 71 and 74% were obtained for the CIFN 27/18 and 18/9 ug groups (diff. n.s.). In contrast, genotype 1 / high viral load patients showed SR rates for the CIFN 27/18 and CIFN 18/9 ug groups of 41 and 49% (diff. sig.), respectively. The viral response rates obtained with daily dosing of CIFN were significantly higher than an independently run control arm using CIFN at 9 ug TIW with ribavirin irrespective of the initial viral load.

Four patients (2%) experienced grade III thrombocytopenias, while no grade IV neutropenias or thrombocytopenias were observed. The overall tolerability in the CIFN 18/9 ug QD arm was comparable to standard therapy with pegylated interferon a2b and ribavirin, while the CIFN 27/18/9 ug arm was less tolerable during the high dosing period. However, the withdrawal rates were not significantly affected by the higher dose of CIFN.
 

Conclusions

CIFN daily dosing / induction therapy in combination with ribavirin thus shows significant response rates with the highest response rates in genotype 1 patients seen to-date. The sustained response rates for genotype 1 / high viral load patients are higher than the ones demonstrated in the PEG Interferon and ribavirin registration trials. These data suggest that for difficult-to-treat genotype 1 / high viral load patients CIFN with daily and higher initial dosing may be a worthwhile alternative to standard combination therapy with pegylated interferons.

11/07/03

Reference
S Kaiser and others. DAILY DOSING REGIMEN OF CONSENSUS INTERFERON AND RIBAVIRIN FOR TREATMENT-NAIVE PATIENTS WITH CHRONIC HEPATITIS C AND GENOTYPE 1. Abstract 304 (poster). 54^th Annual Meeting of the American Association for the Study of Liver Diseases. October 24-28, 2003. Boston, MA.